Alkyne ketones

ABSTRACT

Provided are processes for the preparation of the compound of the formula  
                 
 
     wherein R 1 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, lower alkyl, lower alkoxy, carboxy, C 1 -C 6  trihaloalkyl, and cyano; and R 2  is amino or lower alkyl.  
     Also provided are synthetic intermediates that are useful as intermediates in the preparation of the compound of the formula 1.

[0001] This application is a divisional of U.S. patent application Ser.No. 10/245,949, filed Sep. 18, 2002, which claims the benefit of U.S.patent application Ser. No. 60/323,006, filed Sep. 18, 2001. Thedisclosure of both of these applications are hereby incorporated byreference as if fully set forth herein.

[0002] The present invention relates to processes for the preparation of1,5-diarylpyrazoles, and chemical intermediates that serve as usefulintermediates in the preparation of 1,5-diarylpyrazoles.1,5-Diarylpyrazoles are particularly useful in the treatment ofinflammation and inflammation-related disorders, including arthritis.

[0003] Selective inhibitors of cyclooxygenase-2 (COX-2) havedemonstrated effective anti-inflammatory activity with reducedgastrointestinal side effects, as compared to other antiinflammatoryagents, e.g., NSAIDs, that inhibit both the constitutive form ofcyclooxygenase (COX-1), and the inducible form of the enzyme, COX-2. Aparticularly effective structural class of selective COX-2 inhibitorsare the 1,5-diarylpyrazoles. For example, the compound,4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(celecoxib®) has been approved by the Food and Drug Administration forthe treatment of rheumatoid arthritis and osteoarthritis.

[0004] Penning et al. (J. Med. Chem. 1997, 40, 1347-1365) discloses that1,5-diarylpyrazoles can be prepared by condensation of 1,3-dicarbonyladducts with aryl hydrazines. The 1,3-dicarbonyl adducts can be preparedby Claisen condensations of aryl methyl ketones with carboxylic acidesters. In an alternate preparation, the 1,5-diarylpyrazoles can besynthesized by epoxidation of β-aryl-α,β-unsaturated ketones, followedby condensation of the resulting epoxides with arylhydrazines.

SUMMARY OF THE INVENTION

[0005] In one embodiment, the invention relates to a process forpreparing a compound of the formula

[0006] R¹, R³ and R⁴ are independently selected from the groupconsisting of hydrogen; halogen; preferably fluoro, chloro, bromo oriodo; hydroxyl; nitro; C₁ to C₆ alkyl, preferably C₁ to C₃ alkyl; C₁ toC₆ alkoxy, preferably C₁ to C₃ alkoxy, more preferably methoxy; carboxy;C₁-C₆ trihaloalkyl, preferably trihalomethyl, more preferablytrifluoromethyl; and cyano.

[0007] R² is amino; or lower alkyl, preferably C₁ to C₃ alkyl.

[0008] In preferred aspects, the invention relates to the process forpreparing a compound having the formula

[0009] Preferably R¹ is methyl, particularly where R² is amino.

[0010] The process includes the step of condensing an alkyne of formula

[0011] with a phenyl hydrazine of the formula

[0012] or a salt thereof.

[0013] In some embodiments, the alkyne of the formula 3 is prepared by:

[0014] (i) adding bromine to a compound of formula

[0015] and

[0016] (ii) contacting the product of step (i) with a base.

[0017] In one embodiment, the compound of the formula 2 can be preparedby treating a compound of the formula

[0018] with trimethyl(trifluoromethyl)silane in the presence of cesiumfluoride.

[0019] In an alternative embodiment, the compound of formula 3 can beprepared by a process that includes:

[0020] (i) contacting a phenylacetylene of the formula

[0021] with carbon monoxide, oxygen, and methanol, in the presence of apalladium (II) catalyst to provide a propargylic ester of the formula

[0022] and

[0023] (ii) treating the propargylic ester of the formula 9 withtrimethyl(trifluoromethyl)silane in the presence of cesium fluoride togive the compound of formula 3.

[0024] In another aspect, the invention relates to a compound of theformula

[0025] R¹, R³ and R⁴ are independently selected from the groupconsisting of hydrogen; halogen; preferably fluoro, chloro, bromo oriodo; hydroxyl; nitro; C₁ to C₆ alkyl, preferably C₁ to C₃ alkyl; C₁ toC₆ alkoxy, preferably C₁ to C₃ alkoxy, more preferably methoxy; carboxy;C₁-C₆ trihaloalkyl, preferably trihalomethyl, more preferablytrifluoromethyl; and cyano.

[0026] In a preferred embodiment, the compound has the formula

[0027] wherein R¹ is lower alkyl, preferably methyl.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The following terms shall have, for the purposes of thisapplication, the respective meanings set forth below.

[0029] “lower alkoxy” shall include linear or branched C₁ to C₆ alkoxygroups, unless otherwise specified.

[0030] “lower alkyl” shall include linear or branched C₁ to C₆ alkylgroups, unless otherwise specified.

[0031] In accordance with the present invention, novel processes andsynthetic intermediates for the preparation of 1,5-diarylpyrazoles areprovided. The processes of the invention have been developed fromreadily available and inexpensive starting materials. Furthermore, theprocesses provide high yields of 1,5-diarylpyrazoles, and simplifyisolation and purification steps.

[0032] One embodiment of the invention is depicted in Scheme 1, whereinR¹-R⁴ are as described above for the compound of formula 1, and Y is ahalide, preferably chloride. An alkyne of the formula 3, is condensedwith a phenyl hydrazine compound of the formula 4 to provide a1,5-diaryl-3-trifluoromethylpyrazole of the formula 1. Preferably, thephenyl hydrazine compound of the formula 4 is provided as a salt, e.g.,a hydrochloride salt. The reaction can be completed in a protic solventsuch as ethanol, n-propanol, isopropanol, butanol or acetic acid at anelevated temperature, e.g. ethanol at reflux. Typically a slight excessof phenyl hydrazine is used, from about 1.05 to about 1.3 molarequivalents. The reaction provides high regioselectivity with respect tothe ratio of products obtained of the 1,5-diaryl type (i.e. compound ofthe formula 1) to the 1,3-diaryl type (not shown). Typically, the ratioof the desired 1,5-diaryl pyrazole to the undesired 1,3-isomer isgreater than 9 to 1. Purification of the compound of formula 1 can beconveniently carried out by recrystallization from alcohol solvents,e.g., ethanol.

[0033] Various acid addition salts of the compound of the formula 1 canbe prepared by treatment with an organic or inorganic acid. Preferably,the acid addition salts formed are pharmaceutically acceptable salts,such as those described in U.S. Pat. No. 5,563,165, the disclosure ofwhich is herein incorporated by reference. Suitable base addition saltsof the compound of formula 1, wherein the phenyl group at the 5-positionof the pyrazole ring incorporates a carboxy or hydroxyl substituent.Base addition salts include metallic addition salts, e.g, sodium,potassium, and organic base addition salts, e.g, organic amines. Otherpharmaceutically acceptable acid addition salts are detailed in U.S.Pat. No. 5,563,165.

[0034] The phenyl hydrazine compound of the formula 4 can be preparedfrom substituted anilines of the formula 11, wherein R² is amino orlower alkyl as shown in Scheme 2. Preferably, the aniline contains theamidosulfonyl or alkylsulfonyl group in the para position as shown inthe structural formula for 11. A diazonium salt is formed from thesubstituted aniline by treatment with nitrous acid (e.g., formed fromhydrochloric acid and sodium nitrite). For example, an aqueous mixtureof sulfanilamide and hydrochloric acid is treated with a solution ofsodium nitrite at temperatures below about 5° C. to form thecorresponding diazonium salt. The cold diazonium salt is then treatedwith a reducing agent, e.g., stannous chloride, to provide thesubstituted phenyl hydrazine compound. It will be appreciated thatalternative well-known preparations of phenyl hydrazine compounds canalso be used, for example, preparation from phenyl halides bynucleophilic displacement by hydrazine.

[0035] The alkyne of the formula 3 can be prepared by synthetic methodsthat are depicted in Schemes 3 and 4. In one embodiment, the alkyne ofthe formula 3 is obtained from an α,β-unsaturated ketone precursor, thecompound of formula 2 (Scheme 3). The compound of formula 2, forexample, is first treated with bromine in a suitable inert organicsolvent, e.g. chloroform, at room temperature for a sufficient amount oftime to form an α,β-dibromo intermediate. The crude product obtainedfrom the bromination reaction is subsequently treated with a base suchan alkali metal hydroxide, e.g., potassium, sodium, or lithiumhydroxide, to effect elimination of HBr and provide the alkyne offormula 3. The alkyne of the formula 3 can be further purified by, forexample, recrystallization from suitable solvents, e.g., alcohols, whenthe compound is a solid. Alternatively, the compound of the formula 3can be purified by, for example, chromatography.

[0036] In one embodiment, the compound of formula 2 can be obtained byelectrophilic addition of a vinylogous ester,4-ethoxy-1,1,1-trifluoro-3-buten-2-one, to the substituted phenylcompound of the formula 8. For example, toluene (R¹=methyl) can betreated with an equimolar amount of4-ethoxy-1,1,1-trifluoro-3-buten-2-one in a suitable inert solvent,e.g., dichloromethane, to provide1,1,1-trifluoro-4-(4-methylphenyl)-3-buten-2-one. Typically, a catalyticamount, e.g. <10 mole %, of a Lewis acid, e.g., zinc chloride, is addedto the reaction mixture to catalyze the addition.

[0037] In this embodiment and an all other embodiments suitableprotecting groups, well known in the art, can be used, where necessary,to protect various phenyl substituents (i.e., R¹, R³ and R⁴), which arethen removed later in the synthesis by known methods. Thus, for example,a hydroxyl moiety can be protected as a methyl or silyl ether.Similarly, a carboxy moiety can be protected as an ester if necessary,which can be hydrolyzed in a later in a later synthetic step.

[0038] In another embodiment, the compound of formula 2 is obtained froma cinnamic acid ester of the formula 5, by treatment withtrimethyl(1,1,1-trifluoromethyl)silane and cesium fluoride (Scheme 3).The reaction is carried out neat, or in an inert organic solvent, e.g,dichloromethane, tetrahydrofuran, at a temperature of about 15 to about30 ° C. The cinnamic acid ester can be obtained from a Heck coupling ofa halophenyl compound of the formula 6 (wherein X is Cl, Br, or I,preferably Br or I) with an alkyl acrylate of the formula 7. Thereaction mixture includes a base, e.g., potassium carbonate, and apalladium catalyst. Palladium catalysts for the Heck reaction arewell-known and include palladium(II) acetate. A stabilizing ligand forthe palladium such as triphenylphosphine can be included in the reactionmixture. include A preferred catalyst is Pd—Cu-Mont. K-10 (clay). Thereaction is typically carried out in a dipolar aprotic solvent e.g.,dimethylformamide, at temperatures of about 100 to about 160° C. TheHeck procedure permits regioselective coupling of the alkyl acrylategroup on to the phenyl ring. This procedure is particularly advantageousfor compounds wherein the electrophilic addition of the vinylogous esterto the phenyl precursors 8 described above leads to unfavorable mixturesof regioisomers in the product.

[0039] In another embodiment of the invention, the alkyne of the formula3 is obtained by treatment of a propargylic ester of the formula 9, withtrimethyl(1,1,1-trifluoromethyl)silane and cesium fluoride (Scheme 4).Here again, the reaction is carried out neat, or in an inert organicsolvent, e.g, dichloromethane, tetrahydrofuran, at a temperature ofabout 15 to about 30° C.

[0040] The propargylic ester of the formula 9 can be obtained from aphenylacetylene having the formula 10, wherein R¹ is as described above.The reaction is catalyzed by a palladium (II) catalyst, e.g., palladium(II) acetate, in a methanol at a temperature of about 15° C. to about40° C. Preferably, the reaction catalyzed by a palladium (II) catalyst(e.g., palladium (II) acetate), molybdovanadophosphate (NPMoV), andchlorohydroquinone (HQ-Cl).

[0041] In another embodiment, the propargylic ester of the formula 9,may be obtained by formation of the corresponding anion of the alkynehaving the formula 10, with a strong base, e.g., n-butyllithium, lithiumdiisopropylamide, lithium hexamethyl-disilazide, and addition of theanion to an activated derivative of trifluoracetic acid, e.g,trifluoroacetyl chloride, trifluoroacetic anhydride.

[0042] The following examples further illustrate the present invention,but of course, should not be construed as in any way limiting its scope.

EXAMPLE 1 Synthesis of4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(R¹=p-CH₃ and R²═NH₂, R³═R⁴═H).

[0043] Preparation of 1,1,1-Trifluoro-4-(4-methylphenyl)-3-buten-2-one(2 R¹=p-CH₃, R³═R⁴═H):

[0044] To a solution of toluene (8, R₁=p-CH₃, R³═R⁴═H, 10 mmol) and4-ethoxy-1,1,1-trifluoro-3-buten-2-one (10 mmol) in dichloromethane (10mL) is added zinc chloride (0.015 g, 1.5 mol %). The reaction mixture isstirred for 3 h at 22° C. The resulting precipitate is filtered, washedwith dichloromethane (2×15 mL) and dried.

[0045] Preparation of 1,1,1-Trifluoro-4-(4-methylphenyl)-3-butyn-2-one(3, R¹=p-CH₃, R³═R⁴═H):

[0046] To a stirred solution of1,1,1-trifluoro-4-(4-methylphenyl)-3-buten-2-one (2, 10 mmol) inchloroform (100 mL), a solution of bromine (10 mmol) in chloroform (50mL) is added dropwise at room temperature. The solution is stirred foran additional 30 min to complete of the reaction. The solvent is thenremoved under vacuum to obtain the dibromo compound.

[0047] The dibromo compound is added in portions to a solution ofethanolic (200 mL) potassium hydroxide (10 mmol) over a period of 30min. After the addition is complete, the reaction mixture is refluxedfor 3 h, cooled and poured onto ice cold water. The precipitated1,1,1-trifluoro-4-(methylphenyl)-3-butyn-2-one is separated byfiltration and recrystallized.

[0048] Preparation of 4-Sulfamylphenyl hydrazine Hydrochloride (4,R²═NH₂):

[0049] (A procedure is described in J. Med Chem. 1979, 22, 321-325.) Acold stirred mixture of sulfanilamide (11, 34.2 g, 0.2 mol),hydrochloric acid (100 mL) and crushed ice (200 g) is diazotized bydropwise addition of sodium nitrite (14 g, 0.2 mol) in water (25 mL)over 30 min. The cold diazonium salt thus formed is rapidly added to awell-cooled solution of stannous chloride (100 g) in hydrochloric acid(150 mL) with vigorous stirring, and the resulting mixture is left inthe refrigerator overnight. The precipitated 4-sulfamylphenyl hydrazinehydrochloride is collected at pump and dried.

[0050] Preparation of4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(1, R¹═CH₃, R³═R⁴═H and R ²═NH₂):

[0051] A solution of 1,1,1-trifluoro-4-(methylphenyl)-3-butyn-2-one (3,10 mmol) in ethanol (100 mL) is refluxed with 4-sulfamylphenyl hydrazinehydrochloride (4, 12 mmol) for 4 h. The reaction mixture is cooled anddiluted with water. The precipitated crude4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideis filtered and recrystallized.

EXAMPLE 2 Preparation of 1,1,1-Trifluoro-4-Phenyl-3-Butyn-2-one (3,R¹═H)

[0052] Preparation of Methyl Phenylpropiolate (9 R¹═H, R³═R⁴═H)

[0053] A solution of phenylacetylene (10, 2 mmol),chlorohydroquinone(HQ-Cl) (0.4 mmol), molybdovanadophosphate (NPMOV) (35mg) and palladium (II) acetate (50 mg) in methanol (10 mL) is stirredunder CO/O₂ (10 atm/0.5 atm) at 25° C. for 15 h. The reaction is thenquenched with wet ether and the product is extracted with n-hexane.After removal of the solvent under reduced pressure, the product isisolated by column chromatography over silica gel (hexane:ethyl acetate5:1) to give pure methyl phenylpropiolate.

[0054] Conversion of Methyl Phenylpropiolate (9) to1,1,1-Trifluoro-4-Phenyl-3-Butyn-2-one (3)

[0055] At room temperature, CsF (0.15 g, 1 mmol) is added to a mixtureof methyl phenylpropiolate (9, 1.62 g, 10 mmol) and TMS-CF₃ (1.46 g,10.25 mmol) (Lancaster). After completion of the reaction (3 h),hydrolysis is carried out over 3 h by using 4 N HCl (4 mL). Theresulting product is extracted with ether (30 mL). After removing theether, the trifluoromethylated ketone is obtained.

[0056] While this invention has been described with an emphasis uponpreferred embodiments, it will be obvious to those of ordinary skill inthe art that variations in the preferred devices and methods may be usedand that it is intended that the invention may be practiced otherwisethan as specifically described herein. Accordingly, this inventionincludes all modifications encompassed within the spirit and scope ofthe invention as defined by the claims that follow.

What is claimed:
 1. A compound of the formula

wherein R¹, R³ and R⁴ are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, nitro, lower alkyl, loweralkoxy, carboxy, C₁-C₆ trihaloalkyl, and cyano.
 2. The compound of claim1, wherein the compound of formula 3 has the formula

wherein R¹ is lower alkyl.
 3. The compound of claim 2, wherein R¹ ismethyl.